Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer,c haracterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates.W e designed as eries of novel Au III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely,m etformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au III fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues.These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…These defense processes are damaged by closing mitochondrial breathing and autophagy flux, resulting in the inhibition of protein degradation and apoptosis. 240 Grasa et al synthesized a series of new dithiocarbamate cycloaurated complexes. The cytotoxicity of the human colon cancer cell line Caco-2/TC7 was evaluated in vitro, and complex 335 showed the best antiproliferative activity and excellent selectivity, with IC 50 values of 1.85 AE 0.36 mM for Caco-2/TC7 cells and 12.95 AE 0.11 mM for normal cells.…”

“…This interaction can be responsible for the observed anticancer bioactivity. 231,240,258,259 GR played a pivotal role in cellular redox metabolism and maintained the thiol protein concentration and bioactivity in cells. As we know that the reactive site of the GR enzyme contained cysteine residues, the interaction of gold complexes with cysteine group of GR was particularly important.…”

Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)‐Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells

“…[10,11] Ruthenium compounds have emerged as potential alternatives to classical platinum-based chemotherapeutics for cancer. [12] Recent successful clinical trials with two ruthenium compounds for treating non-muscle invasive bladder cancer (Ru(II)-based photosensitizer TLD1433: [Ru(bpy)(IP-TT)] 2 + , IP-TT = 2-(2',2'':5'',2'''-terthiophene)imidazo [4,5-f] [1,10] phenanthroline) [13,14] and for the treatment of solid tumors in combination therapy (Ru(III) antimetastatic agent BOLD-100: Na[trans-RuCl 4 (Ind) 2 ], Ind = indazole) [15,16] underscore the progress in this field. Ruthenium compounds have shown high efficacy in pre-clinical models in breast cancer [17] including TNBCs mice models .…”

Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases

“…Recently, new organogold derivatives of general formula [Au(C^N)Cl 2 ] (C^N = cyclometalated ligand), being endowed with increased stability in aqueous environment relative to the benchmark inhibitor Auphen ( Casini et al, 2008 ; Bertrand and Casini, 2014 ), were shown to inhibit human AQP10 in a yeast model ( Pimpao et al, 2021 ). Some of the tested gold complexes have been reported to inhibit cancer cells proliferation in vitro ( Bertrand et al, 2015 ) and in vivo ( Babak et al, 2021 ). Thus, the Au(III) C^N complex featuring a metformin ancillary ligand (AuMet, Figure 5 ) was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers.…”